Clinical management and burden of bipolar disorder: results from a multinational longitudinal study (WAVE-bd)

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1 International Journal of Neuropsychopharmacology (2013), 16, CINP 2013 doi: /s Clinical management and burden of bipolar disorder: results from a multinational longitudinal study (WAVE-bd) ARTICLE Eduard Vieta 1, Jens M. Langosch 2, Maria Luisa Figueira 3, Daniel Souery 4, Elena Blasco-Colmenares 5, Esteban Medina 6, Miriam Moreno-Manzanaro 6, Miguel Angel Gonzalez 7 and Frank Bellivier 8 1 Bipolar Disorders Program, Hospital Clínic, University of Barcelona, Barcelona, Spain 2 Bethanien Hospital for Psychiatry, Psychosomatics, and Psychotherapy, Greifswald, Germany 3 Psychiatric Department, Hospital Santa Maria, Faculty of Medicine, University of Lisbon, Portugal 4 Centre Européen de Psychologie Médicale/Psy-Pluriel, Brussels, Belgium 5 Johns Hopkins University Institution, SOM DOM Cardiology, MD, USA 6 Medical Department, AstraZeneca Pharmaceuticals, Madrid, Spain 7 Quintiles, Madrid, Spain 8 AP-HP, GH Saint-Louis-Lariboisière-Fernand Widal, Paris, France Abstract Bipolar disorder is a mood disorder which requires complex treatment. Current treatment guidelines are based on the results of published randomized clinical trials and meta-analyses which may not accurately reflect everyday clinical practice. This multi-national, multi-centre, observational cohort study describes clinical management and clinical outcomes related to bipolar disorder in real-life settings, assesses between-country variability and identifies factors associated with clinical outcomes. Adults from 10 countries in Europe and South America who experienced at least one mood episode in the preceding 12 months were included. Overall, 2896 patients were included in the analyses and followed for at least 9 months across a retrospective and prospective study phase. Main outcome measures were the number and incidence rate of mood episodes (relapses and recurrences) and healthcare resource use including pharmacological treatments. Relapses and recurrences were reported in 18.2 and 40.5% of patients, respectively; however, the reported incidence rate of relapses was higher than that of recurrences [1.562 per person-year (95% CI ) vs per person-year (95% CI )]. Medication use was high during all episode types and euthymia; the percentage of patients receiving no medication ranged from 11.0% in mania to 6.1% in euthymia. Antipsychotics were the most commonly prescribed drug class in all disease phases except for patients with depression, where antidepressants were more frequently prescribed. Visits to the psychiatrist were the most frequently used healthcare resource. These results provide a description of treatment patterns for bipolar disorder across different countries and indicate factors related to relapse and recurrence. Received 24 October 2012; Reviewed 26 November 2012; Revised 26 February 2013; Accepted 3 March 2013; First published online 13 May 2013 Key words: Bipolar disorder, disease management, recurrence, relapse. Introduction Bipolar disorder (BD) is a category of lifelong mood disorders characterized by the presence of one or Address for correspondence: Dr E. Vieta, Director of the Bipolar Disorders Program, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, 170 Villarroel St., 08036, Barcelona, Spain. Tel.: Fax: EVIETA@clinic.ub.es more recurrent episodes of mania, depression and mixed episodes which include both manic and depressive symptoms. BD is estimated to have a prevalence of between 0.2 and 6%, depending on the range of bipolar spectrum disorders included (Hakkaart et al., 2004; Mitchell et al., 2004; Pini et al., 2005; Baldessarini et al., 2007; Saarni et al., 2010). However, it has been noted that complex clinical presentations contribute to high levels of misdiagnosis of BD, mainly as major depressive disorder; therefore,

2 1720 E. Vieta et al. prevalence figures may be underestimates (Kamat et al., 2008; Stensland et al., 2008; Ruggero et al., 2010; Angst et al., 2011). BD has a substantial global burden of disease; the World Health Organization World Health Report on Mental Health acknowledged BD as the ninth leading cause of years of healthy life lost due to premature mortality and disability (disability adjusted life-years) in those aged yr (WHO, 2012a), and in 2004, BD accounted for an estimated 0.9% of the total global burden of disease worldwide (WHO, 2012b). Treatment of patients with BD aims to relieve symptoms, prevent further episodes (relapses and/or recurrences) and to recover previous psychosocial functioning. National and international professional organisations have published treatment guidelines (NICE, 2006; Grunze et al., 2009, 2010, 2013; Yatham et al., 2009; APA, 2012; Crismon et al., 2012) which are generally in agreement regarding clinical management and pharmacological therapy. Available BD treatment guidelines are based on the results of published randomized clinical trials (RCTs) and meta-analysis studies (Nivoli et al., 2011, 2012), which provide vital evidence of efficacy when assessing novel treatments and management practices. However, the design and structure of RCTs have inherent limitations, when viewed in the context of the full disease (Post, 2009). For example, RCTs generally focus on a single disease phase or treatment, although in clinical practice most patients receive multiple drugs across different phases of the disease. Furthermore, RCTs typically exclude patients with severe disease or co-morbidities such as suicidal behaviour, alcohol and drug dependence, or personality and anxiety disorders which are highly prevalent within BD (George et al., 2003; Valtonen et al., 2005; McIntyre et al., 2006; Swann, 2010). The Wide AmbispectiVE study of the clinical management and burden of BD (WAVE-bd) is a pioneering, non-interventional longitudinal study, undertaken to provide accurate and reliable information on the management of patients with BD in conditions representative of everyday clinical practice across different countries in Europe and South America. This study investigates BD from a comprehensive perspective, considering all the phases of the disease in a global population. This allows description of the management of patients with BD across different countries, and identification of the risk factors associated with clinical outcomes such as recurrences and relapses. The design of this study has been reported previously (Vieta et al., 2011a, b). This paper presents the study results for the first time. Method Study design The study design of WAVE-bd has been described in detail in our previously published methodology papers (Vieta et al., 2011a, b). Briefly, WAVE-bd (NCT ) is a multi-national, multi-centre, observational longitudinal study of patients diagnosed with BD type I or type II in any phase of the disorder who had experienced at least one mood event during the 12 months before enrolment. WAVE-bd included a retrospective and prospective phase. The retrospective phase analysed patients medical information from index episode (the first mood episode in the retrospective period, which occurred 12 3 months before study start) to study start. The prospective phase analysed patients medical information between study start and the last visit of the last patient included in the study. Patients spent a variable amount of time in the study depending on the date of their index episode, the date of patient study start, and the length of the enrolment period; study time ranged months. In total, 239 sites were selected across 10 countries (Austria, Belgium, Brazil, France, Germany, Portugal, Romania, Turkey, Ukraine and Venezuela) to obtain a patient population representative of everyday clinical practice. Patients were recruited from both in-patient and out-patient settings (mental health centres, clinics, private settings, hospitals or specialized units) and site selection was based on the percentage of patients that attend different types of sites in each country (Vieta et al., 2011a, b). Site capacity was assessed prior to enrolment and a range of patients to be enrolled was agreed on which would be representative, feasible and provided the final total sample required per site and country. Either every eligible patient identified was invited to participate, or in sites that exceeded the target sample size (e.g. study sites with limited resource capacity and/or high numbers of eligible patients during the recruitment period), a representative sample was randomly selected by electronic application (Vieta et al., 2011a, b). Study objectives The primary objectives of WAVE-bd were to describe clinical management and clinical outcomes related to BD in conditions representative of routine clinical practice in each of the participating countries, and to evaluate the variability between countries and the factors associated with clinical outcomes (such as patient characteristics; country; treatment). Secondary objectives included: estimation of treatment adherence in

3 Clinical management and burden of BD:WAVE-bd 1721 BD and identification of patients at a higher risk of low adherence; assessment of quality of life and functioning of patients with BD in real-life settings; assessment of burden on caregivers; determination of healthcare resource use; estimation of associated factors. The primary study objectives and the secondary objective of healthcare resource use are reported in this paper. Outcome measures Outcome measures are summarized in Supplementary Table S1. Clinical outcomes were evaluated using an electronic adaptation of the National Institute of Mental Health Life Chart Methodology and the Clinical Global Impression for Bipolar Illness Scale (prospective phase only; Spearing et al., 1997; Denicoff et al., 2000; Vieta et al., 2011a, b). The primary evaluation criteria for clinical outcomes were the frequency of mood episodes in terms of syndromic relapses and recurrences, and estimation of factors associated with the number of relapses and recurrences during the study period. Relapse was defined as a mood episode of any polarity within 8 wk of the end of the previous mood episode during the study period. Recurrence was defined as a mood episode of any polarity after 8 wk from the end of the previous mood episode during the study period. Relapses and recurrences were identified according to the judgment of the clinician, and both included episodes of any polarity, in accordance with Hirschfeld et al. (2007). The frequency of suicide attempts during the study period and estimation of factors associated with the number of suicide attempts were also assessed. Clinical management outcomes were pharmacological treatments and nonpharmacological therapies received for BD during the study period, as determined by patient records, the frequency of visits to different types of healthcare resources and estimation of factors related to healthcare resource use. Statistical analysis Sample size was calculated as described previously (Vieta et al., 2011a, b). The frequency of clinical outcomes were determined with incidence rates (IRs), expressed in person-years. Reported IRs for relapses/ recurrences were calculated as the number of times a relapse/recurrence occurred during follow-up (time between the end of the study index episode and the end of study follow-up) divided by the total time (in years). Reported IRs (in person-years) for suicide attempts were calculated as the number of attempts from the onset of the study index episode to the end of study period divided by the total time of exposure in years. To estimate the association of number of relapses, recurrences or suicide attempts with individual patient characteristics, multivariate analysis was performed. The type of model used was pre-specified as Poisson regression (stratifying by centre), with characteristics included in the final model based on clinical relevance and/or impact on the univariate model. Models provided estimates of the IR ratios (IRRs) of the response variable comparing categories of interest adjusted for participant level covariates (country, type of centre, demographics, medical history, disease characteristics and characteristics of index episode). Clinical factors with a mean IRR>1.05 [with confidence intervals (CI) not including 1 and a p value <0.05] were considered to be associated with a higher number of relapses/recurrences/suicide attempts. Clinical factors with a mean IRR<0.95 (with CI not including 1 and a p value <0.05) were considered to be associated with a lower number of relapses/recurrences/suicide attempts. To identify factors associated with healthcare resource use, random-intercept mixed linear regression models were used, adjusted for participant level covariates (country, type of centre, demographics, medical history, disease characteristics and characteristics of index episode), to provide estimates of the adjusted average difference in the incidence of visits per year. As with the multivariate analyses for clinical outcomes, the type of model was pre-specified, and characteristics were included in the final multivariate model based on clinical relevance and/or impact on the univariate model. Clinical factors with a p value <0.05 were considered to be associated with healthcare resource use. The characteristics considered for all multivariate analyses included: country; site characteristics (type of centre); patient demographics (sex, age, race, years of education, professional status, degree of cohabitation, alcohol dependence, drug dependence); medical history (any mental/psychiatric comorbidity, any other medical condition, any family history of mental/psychiatric condition); disease characteristics (type of BD, time from diagnosis, polarity of episode at diagnosis, age at diagnosis, longest period of euthymia since diagnosis, lifetime presence of psychotic symptoms and/or seasonal pattern and/or rapid cycling, previous hospitalizations, suicidal behaviour); study index episode characteristics (polarity of index episode, duration of index episode, presence of psychotic symptoms at index episode, treatments prescribed).

4 1722 E. Vieta et al. Fig. 1. Patient disposition. ecrf, Electronic case report form. Ethics The study was conducted in accordance with ethical principles consistent with the Declaration of Helsinki 2008 revised guidelines and the applicable legislation on non-interventional studies. The study and the informed consent form were reviewed and approved by the leading Ethics Committee in each participating country and all patients gave their informed consent. Results Study sample and baseline characteristics In total, 2965 patients were enrolled in the WAVE-bd study. Of these, 69 were excluded for unsigned or lack of data in the electronic case report form, resulting in 2896 patients being included in the final analysis (Fig. 1). Patient demographics, co-morbidities and bipolar disease history are shown in Table 1. Demographics were broadly similar between countries. Mean (S.D.) age of study participants was 46.7 (13.3) yr, more patients were female (62.0%), and the majority were Caucasian [91.2% overall; >79.3% in all countries except for Venezuela (36.9%)]. In all countries, most patients lived accompanied, with the percentage of patients living alone ranging from 6.2% in Venezuela to 36.9% in France. A total of 19.9% of patients suffered from at least one co-morbid psychiatric disorder, ranging from 1.8% in Brazil to 38.3% in France. Overall, 25.8% of patients had a family history of BD, ranging from 6.0% in Romania to 34.8% in Belgium. The mean (S.D.) duration of prospective follow-up was (173.9) d overall. Turkey and Brazil had the lowest mean prospective follow-up [298.3 (99.4) and (170.2) d, respectively], and Germany the highest [502.1 (153.1) d; Table 1]. The polarity of study index episodes in each country is shown in Fig. 2. The majority of study index episodes were depressive (53.4%), followed by mania (22.0%) and hypomania (16.5%). Depression was the most common type of study index episode for all countries except Turkey, where it was mania (47.4%). Overall, depressive index episodes tended to have a longer duration than manic, hypomanic and mixed index episodes [mean (S.D.) duration: 104 (101) d compared with 70 (81), 67 (67) and 79 (83) d, respectively]. However, duration varied between countries, especially for index episodes of mixed polarity, which had a much longer duration in Latin American countries than in European countries [mean (S.D.) duration was 181 (113) d in Brazil and 185 (136) d in Venezuela vs. a mean duration in Europe ranging from 37 (30) d in Romania to 123 (143) d in Austria]. Clinical outcomes Relapses Relapses were reported by 18.2% of patients during the study period (n = 526; Table 2). The proportion of patients with reported relapse ranged from 6.2% in Turkey to 34.4% in Austria. The IR of reported relapses during the study was per person-year (95% CI ), ranging from (95% CI ) in Turkey to (95% CI ) in Belgium. This relatively high IR demonstrates that patients reporting a relapse were likely to experience more than one relapse over the course of the study. When analysed by polarity, depressive relapses were the most frequent in terms of the number of patients (331 patients, 11.4%) and the IR [0.798 per person-year (95% CI )]. Hypomanic relapses were the second most frequent occurring in 5.9% of patients [171 patients, IR per person-year (95% CI )], followed by manic relapses which occurred in 3.4% of patients (97 patients, IR per

5 Table 1. Patient demographics, co-morbidities, and disease characteristics by country Austria Belgium Brazil France Germany Portugal Romania Turkey Ukraine Venezuela Total n (%) 125 (4.3) 408 (14.1) 164 (5.7) 480 (16.6) 209 (7.2) 512 (17.7) 183 (6.3) 369 (12.7) 221 (7.6) 225 (7.8) 2896 (100) Demographics Male, n (%) 35 (28.0) 178 (43.6) 58 (35.4) 166 (34.6) 85 (40.7) 181 (35.4) 76 (41.5) 171 (46.3) 90 (40.7) 60 (26.7) 1100 (38.0) Age, mean (S.D.) 51.8 (14.5) 50.0 (12.7) 45.0 (12.9) 46.8 (12.5) 50.0 (13.2) 48.5 (13.3) 49.0 (12.1) 38.3 (12.2) 43.1 (12.0) 46.4 (13.1) 46.7 (13.3) Aged <65 yr, n (%) 97 (77.6) 358 (87.8) 155 (94.51) 448 (93.3) 179 (85.7) 448 (87.5) 167 (91.3) 362 (98.1) 214 (96.83) 207 (92.0) 2635 (91.0) Caucasian, n (%) 123 (98.4) 406 (99.5) 130 (79.27) 411 (85.6) 209 (100) 508 (99.2) 183 (100) 367 (99.5) 221 (100) 83 (36.9) 2641 (91.2) Years of education, 12.6 (3.9) 13.2 (4.1) 10.1 (3.6) 11.1 (4.6) 9.7 (5.2) 11.5 (5.2) 12.9 (3.1) 9.9 (4.2) 13.8 (2.5) 11.8 (4.3) 11.6 (4.5) mean (S.D.) Employed, n (%) 45 (36.0) 130 (31.9) 43 (26.2) 209 (43.5) 69 (33.0) 220 (43.0) 40 (21.9) 132 (35.8) 87 (39.4) 88 (39.1) 1063 (36.7) Living alone, n (%) 46 (36.8) 118 (28.9) 14 (8.5) 177 (36.9) 65 (31.1) 69 (13.5) 25 (13.7) 41 (11.1) 35 (15.8) 14 (6.2) 604 (20.9) Not alcohol/drug abusers, n (%) 112 (89.6) 340 (83.3) 151 (92.1) 357 (74.4) 187 (89.5) 463 (90.4) 159 (86.9) 361 (97.8) 195 (88.2) 209 (92.9) 2534 (87.5) Duration of prospective follow-up, mean (S.D.) (170.2) (200.6) (170.2) (181.8) Co-morbidities High blood pressure, n (%) 30 (24.0) 59 (14.5) 17 (10.4) 53 (11.0) 48 (23.0) 78 (15.2) 43 (23.5) 30 (8.1) 32 (14.5) 33 (14.7) 423 (14.6) Diabetes, n (%) 6 (4.8) 42 (10.3) 9 (5.5) 32 (6.7) 18 (8.61) 42 (8.2) 13 (7.1) 20 (5.4) 4 (1.8) 10 (4.4) 196 (6.8) Dyslipidaemia, n (%) 10 (8.0) 55 (13.5) 4 (2.4) 53 (11.0) 22 (10.5) 82 (16.0) 36 (19.7) 30 (8.1) 3 (1.4) 29 (12.9) 324 (11.2) Thyroid disease, n (%) 19 (15.2) 34 (8.3) 15 (9.2) 48 (10.0) 36 (17.2) 34 (6.6) 13 (7.1) 34 (9.2) 8 (3.6) 24 (10.7) 265 (9.2) Obesity, n (%) 15 (12.0) 58 (14.2) 5 (3.05) 60 (12.5) 52 (24.9) 60 (11.7) 31 (16.9) 18 (4.9) 7 (3.2) 42 (18.7) 348 (12.0) Metabolic syndrome, n (%) 2 (1.6) 24 (5.9) 0 (0.0) 27 (5.6) 9 (4.3) 18 (3.5) 6 (3.3) 3 (0.8) 2 (0.9) 22 (9.8) 113 (3.9) Any co-morbid psychiatric 16 (12.8) 105 (25.74) 3 (1.8) 184 (38.3) 55 (26.3) 65 (12.7) 7 (3.8) 53 (14.4) 50 (22.6) 39 (17.3) 577 (19.9) disorder, n (%) Disease characteristics Type BD I, n (%) 86 (68.8) 260 (63.7) 136 (82.9) 285 (59.4) 132 (63.2) 331 (64.7) 165 (90.2) 301 (81.6) 136 (61.5) 157 (69.8) 1989 (68.7) Rapid cycling, n (%) 20 (16.0) 94 (23.0) 16 (9.8) 72 (15.0) 43 (20.6) 86 (16.8) 12 (6.6) 106 (28.7) 30 (13.6) 28 (12.4) 507 (17.51) Seasonal pattern, n (%) 31 (24.8) 91 (22.3) 4 (2.4) 118 (24.6) 31 (14.8) 180 (35.2) 20 (10.9) 135 (36.6) 65 (29.4) 25 (11.1) 700 (24.2) Family history of BD, n (%) 19 (15.2) 142 (53.8) 37 (22.6) 154 (32.1) 37 (17.7) 164 (32.0) 11 (6.0) 100 (27.1) 15 (6.8) 69 (30.7) 748 (25.8) Age (yr) at first symptoms, 32.0 (14.0) 32.4 (13.8) 29.0 (12.2) 31.0 (11.6) 31.4 (12.7) 32.3 (12.6) 38.7 (12.9) 26.3 (32.3) 31.7 (11.6) 29.4 (11.4) 31.1 (12.4) mean (S.D.) Age (yr) at diagnosis, 37.9 (14.8) 36.5 (13.9) 33.3 (12.6) 35.9 (11.8) 35.9 (12.3) 35.8 (12.6) 40.6 (13.2) 27.4 (10.0) 34.9 (11.5) 34.5 (12.6) 34.9 (12.8) mean (S.D.) Patients with previous 93 (74.4) 252 (61.76) 86 (52.4) 336 (70.0) 157 (75.1) 309 (60.4) 168 (91.8) 221 (59.9) 176 (79.6) 146 (64.9) 1944 (67.1) hospitalizations, * n (%) Patients with previous suicide attempts,* n (%) 28 (22.4) 98 (24.0) 48 (28.3) 136 (28.3) 51 (24.4) 78 (15.2) 31 (16.9) 61(16.5) 19 (8.6) 45 (20.0) 595 (20.6) BD, Bipolar disorder. BD-related. * From diagnosis to index episode (153.1) (180.3) (116.8) (99.4) (121.0) (150.3) (173.9) Clinical management and burden of BD:WAVE-bd 1723

6 1724 E. Vieta et al. Patients (%) Aus Bel Bra Fra Ger Por Rom Tur Ukr Ven Total Mania Hypomania Depression Mixed NOS Unknown Missing Fig. 2. Polarity of study index episode by country. NOS, Not otherwise specified; Aus, Australia; Bel, Belgium; Bra, Brazil; Fra, France; Ger, Germany; Por, Portugal; Rom, Romania; Tur, Turkey; Ukr, Ukraine, Ven, Venezuela. the most common type of reported recurrence was mixed recurrence (25.7%). Multivariate Poisson regression analysis (Table 3) identified four risk factors associated with a higher number of recurrences (mean IRR >1.05, p<0.05). These were: current alcohol or drug abuse and/or dependence; a family history of mental illness; experiencing a rapid cycling disease pattern at any time point; being prescribed anxiolytics, sedatives or hypnotics during the study index episode. No variables were found to be associated with a lower number of reported recurrences (mean IRR <0.95). person-year (95% CI: )] and mixed relapses which occurred in 3.0% of patients [86 patients, IR per person-year (95% CI )]. Depressive relapse was the most common type of reported relapse in all countries except Romania, where the most common type of reported relapse was mixed relapse (13.1%). In multivariate Poisson regression analysis (Table 3), seven variables were identified as independent risk factors for a higher number of reported relapses (mean IRR >1.05, p<0.05). These were: recruitment from a primary care centre; at least one suicide attempt from diagnosis to study index episode; the presence of rapid cycling; aged 565 yr; living alone; having a family history of mental illness; being prescribed antidepressants during the study index episode. Variables associated with a lower number of reported relapses (mean IRR <0.95, p<0.05) were recruitment from a mental health centre and an extended period of euthymia from diagnosis to study index episode. Suicide attempts From the onset of the study index episode, 99 patients attempted suicide (3.4% of the study population), and one suicide was reported during the month study period (Table 2). The proportion of patients attempting suicide was lowest in Turkey (0.8%) and Ukraine (1.8%), and was highest in Belgium (5.6%) and France (5.2%). The reported IR of suicide attempts was per person-year (95% CI ), and ranged from (95% CI ) in Turkey to (95% CI ) in Belgium. In multivariate Poisson regression analysis, two variables were identified as independent risk factors for a higher number of suicide attempts (mean IRR >1.05). These were any suicide attempt from diagnosis to study index episode, and being prescribed antidepressants during the study index episode. No variables were found to be associated with a lower number of suicide attempts during this study (mean IRR <0.95). Recurrences Recurrences were reported by 40.5% of patients during the study period (n = 1173), ranging from 20.1% in Turkey to 63.2% in Austria (Table 2). The IR of reported recurrences was per person-year (95% CI ), ranging from (95% CI ) in Turkey to (95% CI ). Depressive recurrences were the most common [23.1% of patients (n=670); IR per person-year (95% CI )], followed by hypomanic [10.1% of patients (n=293); IR per person-year (95% CI )], manic [6.5% of patients (n = 189); IR per person-year (95% CI 0.078; 0.104)] and mixed recurrences [4.8% of patients (n = 139); IR per person-year (95% CI )]. Depressive recurrence was the most common type of reported recurrence in all countries except for Romania, where Clinical management Medication Medication polytherapy was common throughout all phases of the disease; patients were prescribed a mean (S.D.) number of 2.84 (1.49) treatments in mania, 2.61 (1.32) treatments in hypomania, 3.11 (1.53) treatments in depression, 3.17 (1.51) treatments in mixed episodes and 2.87 (1.45) treatments during euthymia. The medications prescribed during each disease phase, analysed by patient, are shown in Fig. 3. Lithium was prescribed in 30% of patients irrespective of disease phase (mania, 33.2%; hypomania, 30.5%; depression, 26.5%; mixed 27.2%; euthymia, 29.0%). Anticonvulsant use was also reasonably consistent across disease phases (mania, 63.1%; hypomania, 60.3%; depression, 59.4%, mixed 66.0%;

7 Clinical management and burden of BD:WAVE-bd 1725 Table 2. Clinical outcomes by country Austria Belgium Brazil France Germany Portugal Romania Turkey Ukraine Venezuela Total n (%) 125 (4.3) 408 (14.1) 164 (5.7) 480 (16.6) 209 (7.2) 512 (17.7) 183 (6.3) 369 (12.7) 221 (7.6) 225 (7.8) 2896 (100) Relapses All 43 (34.4) 102 (25.0) 29 (17.7) 77 (16.0) 58 (27.8) 88 (17.2) 35 (19.1) 23 (6.2) 36 (16.3) 35 (15.6) 526 (18.2) Manic 7 (5.6) 25 (6.1) 5 (3.1) 3 (0.6) 10 (4.8) 15 (2.9) 11 (6.0) 3 (0.8) 6 (2.7) 12 (5.3) 97 (3.4) Hypomanic 15 (12.0) 42 (10.3) 8 (4.88) 25 (5.2) 18 (8.6) 29 (5.7) 5 (2.7) 6 (1.6) 10 (4.5) 13 (5.8) 171 (5.9) Depressive 32 (25.6) 75 (18.4) 18 (11.0) 55 (11.5) 44 (21.1) 55 (10.7) 5 (2.7) 12 (3.3) 18 (8.1) 17 (7.6) 331 (11.4) Mixed 8 (6.4) 11 (2.7) 5 (3.1) 6 (1.3) 4 (1.9) 13 (2.5) 24 (13.1) 0 (0.0) 13 (5.9) 2 (0.9) 86 (3.0) Recurrences All 79 (63.2) 183 (44.9) 47 (28.7) 176 (36.7) 107 (51.2) 224 (43.8) 93 (50.8) 74 (20.1) 90 (40.7) 100 (44.4) 1173 (40.5) Manic 14 (11.2) 28 (6.9) 12 (7.3) 14 (2.9) 13 (6.2) 21 (4.1) 18 (9.8) 23 (6.2) 15 (6.8) 31 (13.8) 189 (6.5) Hypomanic 13 (10.4) 43 (10.5) 14 (8.5) 64 (13.3) 21 (10.1) 62 (12.1) 5 (2.7) 16 (4.3) 33 (14.9) 22 (9.8) 293 (10.1) Depressive 49 (39.2) 118 (28.9) 18 (11.0) 114 (23.8) 83 (39.7) 136 (26.6) 35 (19.1) 30 (8.1) 39 (17.7) 48 (21.3) 670 (23.1) Mixed 8 (6.4) 16 (3.9) 5 (3.1) 11 (2.3) 6 (2.9) 21 (4.1) 47 (25.7) 5 (1.4) 9 (4.1) 11 (4.9) 139 (4.8) Suicide attempts All 3 (2.4) 23 (5.6) 8 (4.9) 25 (5.2) 8 (3.8) 14 (2.7) 5 (2.7) 3 (0.8) 4 (1.8) 6 (2.7) 99 (3.4) n, Number of patients. euthymia, 62.8%). However, there were variations in the type of anticonvulsant used depending on disease phase. Valproic acid was the most commonly used anticonvulsant in all disease phases, being prescribed more frequently in manic (45.3% of patients) and mixed episodes (43.3% of patients) and used less frequently in depression (29.3% of patients). As expected, antidepressant use was highest in depression (71.7% of patients) although a moderately high proportion of euthymic patients were also receiving antidepressants (49.7% of patients). In addition, 16.5% of patients with mania and 32.0% of patients with hypomania also received antidepressants. The most commonly prescribed antidepressants were selective serotonin reuptake inhibitors, followed by serotonin norepinephrine reuptake inhibitors, across all disease phases (Fig. 3). Antipsychotics were the most commonly used drug class in all episode types except depressive episodes, where antidepressants were more commonly prescribed. The percentage of patients that received antipsychotics was 85.2% in mania, 73.3% in hypomania, 63.2% in depression, 74.0% in mixed episodes and 69.7% in euthymia. The use of atypical antipsychotics was far higher than that of typical antipsychotics in these patients (Fig. 3). Anxiolytics, sedatives and hypnotics were prescribed more frequently in mixed episodes (39.1% of patients) and depressive episodes (33.5% of patients) than in mania (23.1% of patients), hypomania (26.7% of patients) and euthymia (28.7% of patients). During the study, 11.0% of patients experiencing a manic episode received no medication. Similarly, the percentage of patients that received no medication in hypomanic, depressive and mixed episodes was 10.4, 7.8 and 6.3%, respectively. Unexpectedly, the phase of the disease where the most patients were prescribed pharmacological treatment was euthymia, where only 6.1% did not receive medication. The percentage of patients who received no medication was comparable between countries for all episode types and was consistently lowest in Turkey. Treatments received were generally similar between countries, overall and according to disease phase (Supplementary Table S2). One notable exception was the proportion of patients treated with lithium during a manic episode which varied considerably between countries, ranging from 3.4% in Romania to 58.3% in Brazil. Atypical antipsychotics were the most common specific treatment in patients during euthymia in all countries except Brazil, where lithium was more commonly used. The longest duration of pharmacological treatment was observed with valproic acid, which patients

8 1726 E. Vieta et al. Table 3. Factors associated with number of reported relapses (a) and recurrences (b) (a) Factor Relapses IRR (95% CI) p value Aged 565 yr ( ) Female ( ) Current alcohol/drug abuser ( ) Living alone ( ) Type BD-I ( ) Familial mental illness ( ) <0.001 Rapid cycling ( ) <0.001 Anxiety disorder ( ) Thyroid disease ( ) Longer period of euthymia since diagnosis ( ) Suicide attempt between diagnosis and index episode ( ) <0.001 Longer time from diagnosis to index episode ( ) Higher no. hospitalizations due to BD since diagnosis ( ) Manic/hypomanic index episode ( ) Depressive index episode ( ) Mixed index episode ( ) Enrolled from hospital ( ) Enrolled from private practice ( ) Enrolled from mental health centre ( ) <0.001 Enrolled from primary care ( ) <0.001 Older age at first BD symptoms ( ) Longer duration between symptoms and diagnosis ( ) Received antidepressants during index episode ( ) (b) Factor Recurrences IRR (95% CI) p value Aged 565 yr ( ) Female ( ) Current alcohol/drug abuser ( ) <0.001 Familial mental illness ( ) Seasonal pattern ( ) Rapid cycling ( ) Anxiety disorder ( ) Thyroid disease ( ) High BP, diabetes or obesity ( ) Longer period of euthymia since diagnosis ( ) <0.001 Suicide attempt between diagnosis and index episode ( ) Longer time from diagnosis to index episode ( ) Higher no. hospitalizations due to BD since diagnosis ( ) Enrolled from hospital ( ) Enrolled from private practice ( ) Enrolled from mental health centre ( ) Enrolled from primary care ( ) Older age at first BD symptoms ( ) Longer duration between symptoms and diagnosis ( ) Received anticonvulsants during index episode ( ) 0.589

9 Clinical management and burden of BD:WAVE-bd 1727 Table 3. (Cont.) (b) Factor Recurrences IRR (95% CI) p value Received antipsychotics during index episode ( ) Received anxiolytics, sedative/hypnotics during index episode ( ) BD, Bipolar disorder; BP, blood pressure; IRR, incidence rate ratio; CI, confidence interval. In total, 1410 relapses and 1332 recurrences were included in the analyses. The IRR is the incidence rate of the stated factor over the opposite factor (defined as all other non-missing data collected). Factors associated with a higher or lower incidence of relapse/recurrence are shown in bold. IRRs with 95% CI were calculated by Poisson regression multivariable analysis adjusted for type of centre, demographics, medical history, disease characteristics and characteristics of index episode. Only clinical factors included in the final model are shown. Countries were included in the model but are not shown. Clinical factors with a mean IRR >1.05 and p value <0.05 were considered factors associated with a higher number of relapses/recurrences. Clinical factors with a mean IRR <0.95 and p value <0.05 were considered factors associated with a lower number of relapses/recurrences. received for a mean (S.D.) length of (262.0) d (Supplementary Table S3). This was followed by lithium [140.7 (260.2) d], quetiapine extended release [79.3 (196.6) d], lamotrigine [76.2 (198.1) d] and olanzapine [62.6 (171.9) d]. Healthcare resource use The frequency of visits to different healthcare centres was measured over the course of the study to assess the burden of BD on healthcare resources. From the onset of the index episode to the end of the study, the IR of visits to all healthcare centres was per person-year (95% CI ). Patient use of healthcare resources was similar between countries, and ranged from IR 7.62 (95% CI ) in Portugal to (95% CI ) in Austria. The most frequently accessed healthcare resource was the psychiatrist [IR 7.51 per person-year (95% CI )] with programmed visits to the psychiatrist more common than spontaneous visits [IR per person-year (95% CI ) vs per personyear (95% CI )]. Programmed visits to psychiatrists were the biggest single healthcare resource used by patients in all countries, with IRs ranging from 5.04 (95% CI ) in Ukraine to 9.42 (95% CI ) in Romania. Other less frequently accessed resources were the psychologist [IR per person-year (95% CI )], primary care [IR per person-year (95% CI )] and group therapy [0.521 per person-year (95% CI )]. The IR of hospitalizations was per person-year (95% CI ) and visits to the emergency room had IR per person-year (95% CI ). In general, patients in Romania, Austria and Germany used healthcare resources most frequently, and patients in Brazil, Venezuela, Turkey, Portugal and Ukraine used healthcare resources less frequently. In multivariate mixed linear regression analysis, variables found to be associated with a higher total healthcare resource use were rapid cycling, thyroid disease, treatment with antipsychotics during the study index episode and a higher number of hospitalizations from diagnosis to the study index episode. The only variable found to be associated with a lower incidence of total healthcare resource use was recruitment from a mental health centre. Discussion This is the primary report from the large WAVE-bd study, which was designed to describe clinical management and clinical outcomes related to BD in real-life settings from different countries. The results indicate that certain disease characteristics tend to be the same across geographical and cultural backgrounds, while others and particularly certain outcomes such as the intensity of care devoted to each illness phase (mania, depression) may change quite substantially depending on the healthcare system of each country. The study shows that relapses are very common ( 18% during the month study, mostly depressive) and that this is a highly recurrent illness, with >40% of the patients experiencing a recurrence during the study, despite the fact that almost all patients (94%) were on maintenance treatment. The high morbidity of BD is well documented (Judd et al., 2003; Perlis et al., 2006; de Dios et al., 2012); analyses carried out in this

10 1728 E. Vieta et al. (a) (b) Patients receiving treatment (%) Lithium Carbamazepine Lamotrigine Valproic acid Benzodiazepines Other Atypical Typical Tricyclic Tetracyclic SSRIs SNRIs NRIs MAOIs Patients receiving treatment (%) Lithium Carbamazepine Lamotrigine Valproic acid Benzodiazepines Other Atypical Typical Tricyclic Tetracyclic SSRIs SNRIs NRIs MAOIs Anticonvulsants Anxiolytics Antipsychotics Antidepressants Anticonvulsants Anxiolytics Antipsychotics Antidepressants (c) Patients receiving treatment (%) Lithium Carbamazepine Lamotrigine Valproic acid Benzodiazepines Other Atypical Typical Tricyclic Tetracyclic SSRIs SNRIs NRIs MAOIs (d) Patients receiving treatment (%) Lithium Carbamazepine Lamotrigine Valproic acid Benzodiazepines Other Atypical Typical Tricyclic Tetracyclic SSRIs SNRIs NRIs MAOIs Anticonvulsants Anxiolytics Antipsychotics Antidepressants Anticonvulsants Anxiolytics Antipsychotics Antidepressants (e) Patients receiving treatment (%) Lithium Carbamazepine Lamotrigine Valproic acid Benzodiazepines Other Atypical Typical Tricyclic Tetracyclic SSRIs SNRIs NRIs MAOIs Anticonvulsants Anxiolytics Antipsychotics Antidepressants Fig. 3. Pharmacological treatments prescribed in each disease phase during the study. Medications prescribed in mania (a), hypomania (b), depression (c), mixed episodes (d), and euthymia (e) are presented. * Percentages for treatment are calculated with regard to patients with at least one manic/hypomanic/depressive/mixed episode or euthymia period with any treatment. MAOI, Monoamine oxidase inhibitor; NRI, noradrenaline reuptake inhibitor; SNRI, serotonin norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. study indicate that factors leading to relapses and recurrences include alcohol/drug abuse, family history of mental illness, rapid cycling, short duration of euthymia, previous suicide attempts and more hospitalizations. This is consistent with previous literature; several small studies and a few large ones have observed that patients with substance use co-morbidity are more likely to recur and to be poorly adherent to medication (Colom et al., 2000; Mantere et al., 2010; Ostacher et al., 2010). Moreover, family

11 Clinical management and burden of BD:WAVE-bd 1729 history has been reported to be relevant to outcome (Romero et al., 2007; Baldessarini et al., 2012), and rapid cycling is a well-known factor leading to poor short- as well as long-term outcome (Lee et al., 2010; Undurraga et al., 2012). Short periods of euthymia may be a proxy of subclinical symptoms, which have been consistently reported to predict recurrences (Perlis et al., 2006). Our study highlights an association between use of antidepressants (during the index episode) and an increased risk of both relapse and suicide attempts. This could be interpreted as representing patients with depressive symptoms; these patients being more prone to relapse, recurrence or suicide attempt. However, as a relatively high number of patients in manic and hypomanic phases of the disease also received antidepressants, this association may also reflect that antidepressant use is a risk factor for relapse, recurrence or suicide attempt in this group of patients. An excessive use of antidepressant has also been reported in other surveys (Grande et al., 2012). Suicide attempts have also been reported to be more frequent in patients who are more prone to relapse (Bellivier et al., 2011) and hospitalizations obviously correlate with recurrences. The Predictors of Recurrence in Bipolar Disorder in Spain study (de Dios et al., 2012) identified other factors, such as living in rural or small urban areas, and being severely disabled, as predictive factors for relapse and recurrence, which were not confirmed in this study. Taken together, the predictors identified in this study are clinical markers of longitudinal severity, which confirm the findings of previous studies. The findings concerning medication are somewhat less obvious: the mean number of drugs per patient was about three, confirming that polytherapy is the rule rather than the exception, regardless of guideline recommendations (Nivoli et al., 2011, 2012). Prescription patterns indicate that clinicians are aware that anticonvulsants are not a class in BD (Fountoulakis et al., 2011; Rosa et al., 2011), given the sharp differences in patients profile among valproate, carbamazepine and lamotrigine. Another relevant finding is the low rate of lithium use in all phases of the disease, although lithium has been considered by many the cornerstone of the treatment of manicdepressive illness (Nivoli et al., 2010). This may be the result of varying cultural differences in prescription and marketing across countries; in some countries, lithium may be perceived as unsafe because of the risk of intoxication, which might have been emphasized by competitors in certain places. Lithium is an orphan drug and is not promoted at all nowadays. The use of antidepressants was very high ( 50% in maintenance) despite the very limited evidence base supporting that practice (Fountoulakis et al., 2011; Pacchiarotti et al., 2011). Even 16% of manic patients received antidepressants, as reported independently by Rosa et al. (2011) in the European Mania in Bipolar Longitudinal Evaluation of Medication study (Rosa et al., 2010) and despite concerns about drugs of this class exacerbating manic symptoms (Perlis et al., 2010; Valentí et al., 2012). Hence, prescribers seemed to have little awareness of the risk of switch into mania or mixed episodes (Valentí et al., 2011, 2012; Undurraga et al., 2012) or, if they were, they seemed to prefer to take the risk rather than avoiding the use of antidepressants. However, the study shows lower antidepressant prescription trends than a US study (Baldessarini et al., 2008) and wider use of antipsychotics across all phases, including depression. The use of antipsychotics beyond the traditional mania indication may reflect the increasing evidence base for their use in maintenance (Vieta et al., 2011) and, in some cases, in depression (Cruz et al., 2010). Another striking finding was the greater use of anxiolytics in patients with mixed episodes, suggesting a clear link between anxiety and mixed features as reported by Koukopoulos (1995), Young et al. (1993) and González-Pinto et al. (2012). The findings of this study also indicate that BD is a source of clinical burden, which is linked to a high healthcare resource use; the incidence of visits to the psychiatrist was 7.5 per person-year and the incidence of total visits to psychiatrist, psychologist, primary care, group therapy and emergency room was 11.2 per person-year. Despite the large sample size and all the efforts to include a representative sample of patients from every country, this study has limitations. In terms of generalizability, the study did not involve countries from all over the world but selected countries from Europe and South America and, as pointed out previously, important differences between countries exist. Therefore, the results can be considered representative of everyday clinical practice in the selected countries but not beyond those. The study was naturalistic and the diagnosis was made according to DSM-IV criteria, but no standardized interview was used. However, the study population consisted of BD patients with a disease duration of several years, suggesting that diagnostic confidence was high. In addition, a number of scales and systematic assessments were made concerning course and outcome (life chart, Functional Assessment Short Test Scale, Clinical Global Impressions and several other scales as reported previously; Vieta et al., 2011).

12 1730 E. Vieta et al. Baseline information on factors such as weight and smoking status is also lacking. Another major limitation of the study is that suicides were not recorded, so only attempted suicides could be detected. The report of only one suicide was by chance and is lower than previously published data (Tondo et al., 2007; Dennehy et al., 2011). It is likely that more suicides occurred in the lost-to-follow-up group. In summary, the WAVE-bd study provides insights into the treatment patterns for BD across different countries in Europe and South America, and on factors related to relapse and recurrence. The study highlights the increasing use of antipsychotics in BD and the variation in lithium prescription between countries. Combinations of several drugs are commonly used beyond acute episodes and this may be closely related to the high use of healthcare resources found to be associated to this condition. Acknowledgements This study was funded by AstraZeneca. Susie Parker of Fishawack Communications Ltd provided medical writing support, funded by AstraZeneca. The authors are grateful to the investigators involved in the study. [Clinicaltrials.gov registration number NCT , Study of the Clinical Management of Bipolar Disease (WAVE bd), NCT ] Statement of Interest E. Vieta has received grants and served as consultant, advisor or CME speaker for Almirall, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Research Institute, Gedeon Richter, GlaxoSmithKline, Janssen-Cilag, Jazz, Johnson & Johnson, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, Pierre-Fabre, Roche, Qualigen, sanofi-aventis, Servier, Schering-Plough, Solvay, Takeda, Teva, the Spanish Ministry of Science and Innovation (CIBERSAM), the Seventh European Framework Programme (ENBREC), the Stanley Medical Research Institute and United Biosource Corporation and Wyeth. M. L. Figueira has served as a consultant, advisor or speaker for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen-Cilag, sanofi-aventis, Servier, Pfizer, Pierre-Fabre and Lundbeck. She has received grants from The Foundation for Science and Technology (Ministry of Science, Portugal). F. Bellivier has received grants and served as consultant, advisor or speaker for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, sanofi-aventis, Euthérapie, Janssen-Cilag, Lundbeck, Otsuka and the European Space Agency. D. Souery has been a member of advisory boards for AstraZeneca, Lundbeck, Bristol-Myers Squibb, and Eli Lilly and has received an unrestricted grant from Lundbeck. He is involved in clinical trials supported by Eli Lilly, Novartis, and AstraZeneca. J.M. Langosch has received lecture fees from AstraZeneca, Pfizer, Wyeth, Janssen-Cilag, Eisai and reimbursements for being an advisory board member for AstraZeneca and Bristol-Myers Squibb. E. Medina is a previous employee of AstraZeneca. M. Moreno-Manzanaro is an employee of AstraZeneca. M.A. Gonzalez is an employee of the research organization Quintiles; performed statistical analyses; had full access to the raw data set and received funding from AstraZeneca for conducting the analyses. Supplementary material For supplementary material accompanying this paper, visit References American Psychiatric Association (2012) Practice guideline for the treatment of patients with bipolar disorder. Second edition. Bipolar2e_Inactivated_ pdf. Retrieved 27 Feb Angst J, Azorin JM, Bowden CL, Perugi G, Vieta E, Gamma A, Young AH (2011) Prevalence and characteristics of undiagnosed bipolar disorders in patients with a major depressive episode: the BRIDGE study. Arch Gen Psychiatry 68: Baldessarini R, Henk H, Sklar A, Chang J, Leahy L (2008) Psychotropic medications for patients with bipolar disorder in the United States: polytherapy and adherence. Psychiatr Serv 59: Baldessarini RJ, Leahy L, Arcona S, Gause D, Zhang W, Hennen J (2007) Patterns of psychotropic drug prescription for U.S. patients with diagnoses of bipolar disorders. Psychiatr Serv 58: Baldessarini RJ, Tondo L, Vazquez GH, Undurraga J, Bolzani L, Yildiz A, Khalsa HM, Lai M, Lepri B, Lolich M, Maffei PM, Salvatore P, Faedda GL, Vieta E, Tohen M (2012) Age at onset vs. family history and clinical outcomes in 1665 international bipolar-i disorder patients. World Psychiatry 11: Bellivier F, Yon L, Luquiens A, Azorin JM, Bertsch J, Gerard S, Reed C, Lukasiewicz M (2011) Suicidal attempts in bipolar disorder: results from an observational study (EMBLEM). Bipolar Disord 13: Colom F, Vieta E, Martinez-Arán A, Reinares M, Benabarre A, Gastó C (2000) Clinical factors associated with treatment noncompliance in euthymic bipolar patients. J Clin Psychiatry 61: